The composition of the cerebrospinal fluid and brain are closely regulated by mechanisms in the central nervous system that tend to accumulate substances necessary for brain functioning as vitamins and to exclude many unnecessary substances as water-soluble drugs. However, a few water-soluble drugs as lidocaine and the antihistamine, dipenhydramine, tend to enter the central nervous system and cause unwanted central nervous system side effects. The objects of the proposed studies are: 1) to gain further development and function of these transport mechanisms in healthy animals as well as those with experimentally induced diseases as uremia; 2) to gain insight into the biochemical mechanisms underlying these transport processes; 3) to manipulate or work around these transport mechanisms to the diseased animals (and ultimately the patient's) advantage, and 4) to see if reasons for the central nervous system toxicity of lidocaine and diphenhydramine are related to carrier-mediated transport into the central nervous system. Particular attention will be devoted to transport processes and mechanisms located in the choroid plexus. Riboflavin and thymidine pharmacokinetics in the central nervous system will be studied intensively. To achieve these goals, the transport of radiolabeled drugs and vitamins into and out of the cerebrospinal fluid, choroid plexus and brain, in vivo, and into the choroid plexus and brain slices, in vitro, in both normal animals as well as those with uremia will be documented under various conditions.